Epstein-Barr Virus-Positive Mucocutaneous Ulcers Complicate Colitis Caused by Immune Checkpoint Regulator Therapy and Associate With Colon Perforation.

BACKGROUND & AIMS: Cancer therapy with immune checkpoint inhibitors can cause colitis and colon perforation. We investigated whether infection with Epstein Barr virus (EBV) associates with development and severity of colitis in patients receiving immune checkpoint inhibitor therapies. METHODS: We performed a retrospective analysis of fixed colon tissues from 16 patients (12 men, 4 women, median age, 69.5 y) with colitis after immune checkpoint inhibitor therapy (9 patients treated with anti-CTLA4, 3 patients treated with anti-PD1, and 4 patients received a combination). Ten tissue samples were biopsies and 6 were collected during resection (4 surgeries for colon perforation). Patients were treated between 2010 and 2018 in the United Kingdom. The tissues were analyzed by pathology, in situ hybridization (to detect EBV-encoded small RNAs [EBERs]), and immunohistochemistry. Clinical data were also collected. RESULTS: Colon tissues from 4 of the 13 patients who received anti-CTLA4 (alone or in combination, 4 with colon perforation) had EBV-positive lymphoproliferations that manifested as florid ulcers associated with polymorphous infiltrates containing EBV-positive blasts (CD30+ or CD30-negative, CD20+, CD3-negative, and EBER+), plasma cells (CD138+, CD20-negative, and EBER+ or EBER-negative), and small B cells (CD20+, CD3-negative, and EBER+ or EBER-negative), consistent with EBV-positive mucocutaneous ulcers (EBVMCUs). In analyses of biopsies collected from 2 patients with EBVMCUs over multiple time points, we found that earlier biopsies had no or only a few EBV-positive cells, whereas 1 later biopsy had EBVMCU and co-infection with cytomegalovirus. EBVMCUs were associated with steroid-refractory colitis (100% of EBV-positive patients vs 12.5% of EBV-negative patients; P = .008) and colon perforation (100% of EBV-positive patients vs no EBV-negative patients; P = .001). CONCLUSIONS: We found that colon tissues from 4/13 patients with colitis after anti-CTLA4 therapy (4/6 patients who underwent resection and 4/4 patients with colon perforation) contained EBVMCUs. EBVMCUs seem to arise secondarily in areas of inflamed colon due to immunosuppressive treatment for colitis. EBVMCUs are associated with steroid-refractory colitis and colon perforation.

Sugar sensor genes in the murine gastrointestinal tract display a cephalocaudal axis of expression and a diurnal rhythm.

Distributed along the length of the gastrointestinal (GI) tract are nutrient sensing cells that release numerous signaling peptides influencing GI function, nutrient homeostasis and energy balance. Recent studies have shown a diurnal rhythm in GI nutrient sensing, but the mechanisms responsible for rhythmicity are poorly understood. In this report we studied murine GI sugar sensor gene and protein expression levels in the morning (7 AM) and evening (7 PM). Sweet taste receptor ( tas1r2/tas1r3/gnat3/gnat1) sugar transporter ( slc5a1, slc2a2, slc2a5) and putative sugar sensor ( slc5a4a and slc5a4b) gene expression levels were highest in tongue and proximal and distal small intestine, respectively. Clock gene ( cry2/arntl) activity was detected in all regions studied. Slc5a4a and slc5a4b gene expression showed clear diurnal rhythmicity in the small intestine and stomach, respectively, although no rhythmicity was detected in SGLT3 protein expression. Tas1r2, tas1r3, gnat1, and gcg displayed a limited rhythm in gene expression in proximal small intestine. Microarray analysis revealed a diurnal rhythm in gut peptide gene expression in tongue (7 AM vs. 7 PM) and in silico promoter analysis indicated intestinal sugar sensors and transporters possessed the canonical E box elements necessary for clock gene control over gene transcription. In this report we present evidence of a diurnal rhythm in genes that are responsible for intestinal nutrient sensing that is most likely controlled by clock gene activity. Disturbances in clock gene/nutrient sensing interactions may be important in the development of diet-related diseases, such as obesity and diabetes.

Eosinophilic oesophagitis.

Eosinophilic oesophagitis is a chronic immune-mediated inflammatory disorder of the oesophagus, characterized by symptoms of dysphagia or food bolus obstruction. Diagnosis is supported by typical histological findings. This article covers pertinent aspects of the disease, pathogenic explanations and treatment options.

Differences in intestinal metaplasia in Barrett's esophagus patients in an ethnically diverse south London population.

Barrett's esophagus (BE) is the replacement of any portion of the normal distal squamous epithelial mucosa by metaplastic columnar epithelium and is the only known precursor for esophageal adenocarcinoma. We undertook a study to identify ethnic differences for the presence of intestinal metaplasia (IM) in BE in patients in an ethnically diverse south London population. Retrospective analysis was done using the endoscopy database of St George's Hospital NHS Trust, which serves a large ethnically diverse London population. Gastroscopy records between 2009 and 2012 were retrieved, and patients with an endoscopic diagnosis of BE were identified. Patients of Indian subcontinent Asian origin (ISCA) were further identified. The presence of IM was retrieved from hospital pathology databases and was the primary outcome measured. Multivariate logistic regression analysis was performed to determine the odds of having IM by ethnic origin. ISCAs were 70% less likely to have IM compared to non-ISCAs (OR 0.32, 95% CI: 0.16-0.61, p = 0.001). This is the first study to identify differences in histological findings in ISCAs with BE living in the UK. Our findings may be useful for the future risk stratification of BE patients. Identification of environmental factors responsible for this difference would be of great therapeutic value.

New Barrett's oesophagus surveillance guidelines: significant cost savings over the next 10†years on implementation.

OBJECTIVE: We aimed to estimate the cost saving (over the next 10 years) by our trust implementing the new British Society of Gastroenterology (BSG) surveillance guidelines for Barrett's oesophagus (BO). DESIGN: Retrospective endoscopy database analysis. SETTING: Two endoscopy units of St George's Hospital NHS Trust, London. PATIENTS: Gastroscopy records between 2009 and 2012 were retrieved and patients with an endoscopic diagnosis of BO were identified. BO segment length was recorded and the presence (or absence) of intestinal metaplasia in the oesophageal biopsy samples was reviewed from pathology databases. Patients were then stratified into risk groups in accordance with the new BSG guidelines. INTERVENTIONS: Nil. MAIN OUTCOME MEASURES: The projected surveillance costs using the new and the old guidelines were calculated over the next 10 years and the cost saving by the implementation of the new guidelines thus determined. RESULTS: The 10 year projected cost saving for our trust by implementing the new BO surveillance guidelines was £720 330 (or £72 033 per annum). Projected across the NHS, implementation of the new guidance may save £100 million over the next 10 years. CONCLUSIONS: All trusts should review their Barrett's surveillance population and implement these new recommendations expeditiously.